1. Field of the Invention
The present invention relates to oral mouth rinse formulations and, more particularly, to antibacterial oral mouth rinse formulations having enhanced antibacterial activity against oral bacteria associated with infectious and inflammatory processes involved in atherosclerotic plaque formation and coronary artery disease.
2. Description of Related Art
Atherosclerosis is the leading cause of death and disability in the developed world. Coronary artery disease is caused by atherosclerosis, which is a narrowing of the coronary arteries due to fatty build-up of plaque. The conventional risk factors for atherosclerosis have long been known, such as dyslipidemia, hypertension, smoking, diabetes and family history. These risk factors, however, fail to account for approximately 50% to 70% of atherosclerotic events in the general population. Many other putative risk factors for atherosclerosis have been proposed, including traits related to obesity, inflammation and infection.
Periodontal disease is a candidate risk factor for atherosclerosis that shares many of these related traits. The periodontal diseases reflect a spectrum of oral pathology from gingivitis (gum inflammation) to severe periodontitis (progressive loss of gum attachment) with alveolar bone and tooth loss.
The pathogenesis of periodontal disease is thought to be due to accumulation of dental plaque (bacteria in subgingival biofilms) with consequent mucosal infection and inflammation. Abnormal host responses, with upregulation of matrix metalloproteinases, contribute to a more rapid disease progression in some patients. Periodontal disease is more common with cigarette smoking, obesity and diabetes, and it affects about 75% of the adult population in the United States, with about 20% to 30% of adults having severe forms (Al-Zahrani, M.S. et al., J. Periodontol., 74:610-615, 2003). Lack of oral hygiene is recognized as a cause of dental caries, plaque formation and periodontitis. Additionally, lack of oral hygiene can result in systemic effects, including a decline in general health, impairment of the immune system and increased respiratory infections.
Increasing evidence over the past decade suggests a link between periodontal disease and atherosclerosis. Indeed, oral bacteria have been cultured in coronary artery plaques and thus are believed to contribute to the progression of coronary artery disease by increasing inflammation and immune system components of inflammation.
Multiple cross-sectional studies have demonstrated a higher incidence of atherosclerotic complications in patients with periodontal disease, and severe periodontal disease has been shown to be associated with an almost four-fold higher incidence of myocardial infarction compared to patients without periodontal disease (Arbes, S. J., Jr. et al., J. Dent. Res., 78:1777-1782, 1999). Cross-sectional studies also have shown that cardiovascular risk associated with periodontal disease is dependent on the severity of the periodontal disease and independent of the aforementioned conventional risk factors (Armitage, G. C., Oral Disease, 6:335-350, 2000). For example, several case-control studies have indicated that subgingival periodontal pathogenic infection may be associated with myocardial infarction (Genco, R. et al., J. Amer. Dent. Assoc., 133 Suppl:14S-22S, 2002).
Additionally, several prospective longitudinal studies have demonstrated a 1.5 to 2.5-fold increased risk of developing complications of atherosclerosis among patients with periodontal disease (Morrison, H. I. et al., J. Cardiovasc. Risk, 6:7-11, 1999; Wu, T. et al., Arch. Int. Med., 160:2749-2755, 2000). Other studies have shown a thrombogenic role for the oral bacteria Streptococcus sanguis, contributing to the development of the vegetative lesion in infective endocarditis and a thrombotic mechanism to explain the additional contributed risk of periodontitis to myocardial infarction (Herzberg, M. C. et al., J. Periodontol., 67(S10):1138-1142, 1996).
The presence of periodontal infection is believed to lead to brief episodes of bacteremia with inoculation of atherosclerotic plaques by periodontal pathogens such as Porphyroinonas gingivalis, Actinobacillus actinomycetemcomitans and Bacteroides forsythus. Subsequent growth of these bacteria then may cause inflammation and atherosclerotic plaque instability. Indeed, there is evidence, using immunostaining and polymerase chain reaction for bacterial rDNA, that these pathogens are present in 18% to 30% of carotid atheromas (Haraszthy, V. I. et al., J. Periodontol., 71:1554-1560, 2000).
Common oral bacteria that contribute to dental caries, periodontitis and transient bacteremia include the following: Streptococcus mutans, a gram-positive bacterium and the primary etiological agent of dental caries, which possesses several virulence factors that allow it to accumulate within the dental biofilm and produce and tolerate acids which cause caries lesions; Porphyromonas gingivalis, a gram-negative, anaerobic pathogenic oral bacterium, which is a major etiological agent in the initiation and progression of severe forms of periodontal disease. Infection with P. gingivalis may predispose an individual to more serious systemic conditions, such as cardiovascular disease and to delivery of preterm infants; Treponema denticola, an obligate anaerobic bacterium found in the oral cavity of humans and typically associated with periodontal disease. T. denticola DNA and antigens have been detected in atherosclerotic lesions of the aorta in human patients. T. denticola infection of expectant mothers also may cause delivery of preterm infants; Fusobacterium nucleatum, an anaerobic gram-negative oral bacterium found in the normal flora of the mouth, which has been shown to play a role in periodontal disease. Although F. nucleatum is not considered a major dental pathogen on its own, it can adhere to a wide range of other plaque organisms, such as P. gingivalis, and contribute to the development of periodontitis as well as invasive human infections of the head and neck, chest, lung, liver and abdomen; Prevotella intermedia, a bacterium that forms an association complex with other oral bacteria and which virulence factors have been identified, such as hemagglutinating, hemolytic and hemoglobin-binding activities. Clinical isolates of P. intermedia have shown resistance to antibiotics, and thus this bacterium may be one of the more drug-resistant periodontal pathogens; and Actinobacillus actinomycetemcomitans, a facultative oral anaerobic bacterium, which has been shown to be strongly associated with localized juvenile periodontitis.
Improved oral hygiene has lead to a substantial decrease in the incidence of dental caries and periodontal disease over the last half century. During the same time period, however, the incidence and prevalence of atherosclerosis, coronary artery disease and associated myocardial infarction has increased markedly. Interestingly, live oral bacteria have been detected in coronary artery plaques.
Bacteremia has long been known to occur during dental treatment, such as tooth extractions, gum procedures and even tooth cleaning. Indeed, individuals at risk for valvular vegetations, including those individuals with mitral valve prolapse, routinely receive prophylactic antibiotics before dental treatment.
Bacteremia also is known to occur following oral hygiene activities, such as tooth brushing and flossing. Because such bacteremia has been assumed to be transient and inconsequential, no prophylaxis or treatment typically has been recommended for these activities. However, bacteremia associated with oral bacteria may result in inflammatory processes in various regions and systems of the body such as the circulatory system, contributing to diseases of the affected organs or body sites. For example, daily transient bacteremia caused by liberation of oral bacteria from the oral cavity into the circulation may contribute to inflammatory processes associated with autoimmune disorders and other disorders/diseases, such as rheumatoid arthritis, multiple sclerosis and Alzheimer's disease.
Additionally, it is known that individuals with poor oral hygiene, i.e., individuals that only occasionally brush their teeth and rarely tooth floss, and thus have an increased bacterial load in the oral cavity, have an increased risk for coronary artery disease. This may be due, in part, to the transient bacteremia that occurs when the individual does brush and/or floss, which bacteria in the circulation inoculates atherosclerotic plaques.
It also is known that poorly-controlled diabetic individuals have an increased risk for coronary artery disease. This may be due, in part, to the increased glucose levels present in the body fluids of the diabetic individuals, such as saliva. The increased bacterial load in the saliva of diabetics contributes to excessive growth of oral bacteria, which leads to transient bacteremia subsequent to tooth brushing and/or flossing.
There exists a need, therefore, to inhibit the transient bacteremia associated with routine oral hygiene activities of tooth brushing and tooth flossing, which bacteremia may be a significant risk factor for atherosclerosis and associated coronary artery disease, myocardial infarction and death, as well as other inflammatory processes, disorders and diseases in the body.